Benzopyran compounds as 5HT2C receptor antagonists

ABSTRACT

Compounds of formula (I): ##STR1## in which: n represents 1 or 2, 
     R 1  represents hydrogen or alkyl, benzyl, acetyl, benzoyl, allyl, pyridinecarbonyl, pyridinemethyl, acylaminoalkyl (optionally substituted), pyridineaminocarbonyl, phthalimidoalkyl, thiochromanyloxyalkyl or (benzodioxanyloxy)alkyl, 
     R 2 , R 3  or R 4 , which may be identical or different, represent hydrogen or halogen or alkyl, alkoxy, hydroxyl, acetyl, aminocarbonyl, aminomethyl, cyano, nitro, amino, phenyl (which may or may not be substituted), furyl, pyridinyl, thienyl or pyridyl, or alternatively, 
      when they are located on adjacent carbons, R 2  and R 3  form, with the carbon atoms which bear them, a furan or phenyl ring, 
     the isomers thereof and the addition salts thereof with a pharmaceutically acceptable acid, and medicinal products containing the same are useful for the treatment of diseases requiring a ligand to the 5-HT 2C  receptors.

BACKGROUND OF THE INVENTION--PRIOR ART

Besides the fact that they are novel, the compounds of the presentinvention have particularly advantageous properties by selectivelybinding to the 5-HT_(2C) serotoninergic receptors with respect to the5-HT_(2A) receptors. This novel property has never been demonstrated forthe most closely related compounds of the prior art such as, forexample, those described in patents WO 9006927, EP 410,535, EP 539,209or EP 95666.

FIELD OF THE INVENTION

It is well established that the ascending serotoninergic, dopaminergicand adrenergic pathways projecting towards the limbic system and thecortex play a deciding role in controlling mood and in the etiology andtreatment of psychiatric diseases such as schizophrenia, depression andanxiety, as well as aggression and other impulse disorders (M. J. Millanet al., Drug News & Perspectives, 5, 397-406, 1992; A. Y. Dentch et at.,Schizophrenia, 4, 121-156, 1991; H. Y. Meltzer and J. F. Nash,Pharmacol. Rev., 43, 587-604, 1991). These pathways express theiractions by a multitude of different receptors, and increasingly greaterefforts are being made in order to identify the types of receptorsinvolved in these diseases. It is thus hoped that by modifying theiractivity with agonists or antagonists, correction of disordersreflecting dysfunction of the monoaminergic systems may be achieved.

As regards serotonin (5-HT), at least 7 different types of receptorshave been cloned, although present understanding at the functional levelis fairly limited for several of them. Nevertheless, for the twosubtypes of 5-HT₂ receptors which are present in the brain, 5-HT_(2A)and 5-HT_(2C), good indications exist that they are more particularlyinvolved in controlling mood (J. F. W. Deakin, Pharmacol. Biochem.Behav., 29, 819-820, 1988) as well as in the modulation of severalphysiological functions such as the appetite (G. A. Kennett et at., Eur.J. Pharmacol., 164, 445-454, 1989), sleep (C. Dugovic et at.,Psychopharmacology, 97, 436-442, 1989), sexual behavior (H. H. G.Berendsen et at., Psychopharmacology, 101, 57-61, 1990), motor activity(G. A. Kennett and G. Curzon, Psychopharmacology, 96, 93-100, 1988) andcardiovascular functioning (I. K. Anderson et at., Br. J. Pharmacol.,107, 1020-1028, 1992). Consequently, in animals, activation of the5-HT_(2C) receptors appears to bring about, for example, a decrease inthe motor activity (I. Lucki et at., J. Pharmacol. Exp. Ther., 249,155-164, 1989) and a reduction in food intake (S. J. Kitchener and C. T.Dourish, Psychopharmacology, 113, 369-377, 1994), whereas in animals orin man, antagonism of the 5-HT_(2A/2C) receptors is associated withanxiolytic effects (G. A. Kennet et at., Eur. J. Pharmacol., 164,445-454, 1989, D. L. S. Ceuleumans et al., Pharmacopsychiatry, 18,303-305, 1985), antidepressant effects (F. Jenck et al., Eur. J.Pharmacol., 321, 223-229, 1993) and anti-schizophrenic effects (D. L. S.Ceuleumans et al., J. Pharmacol. Exp. Ther., 85, 329-332, 1985).Moreover, blocking of the 5-HT_(2A/2C) receptors appears to be involvedin the atypical profile of the antipsychotic agent clozapine (A. Y.Deutch et al., Schizophrenia, 4, 121-156, 1991).

In view of their very great similarity, it has been extremely difficultto differentiate between the actions induced by the 5-HT_(2A) receptorsand those of the 5-HT_(2C) receptors. Furthermore, for a long time, noantagonist existed which was selectively interactive with 5-HT_(2A)receptors or with the 5-HT_(2C) receptors. Thus, the recent discovery ofa selective 5-HT_(2A) antagonist, MDL 100,907, and of a selective5-HT_(2C) antagonist, SB 200,646, has aroused much interest (Sorensen etal., J. Pharmacol. Exp. Ther., 1993). The first results obtained withthe compound SB 200,646 showing its anxiolytic properties allow aparticularly important role of the 5-HT_(2C) receptors to be envisagedin controlling mood (G. A. Kennett et al., Br. J. Pharmacol., 111,797-802, 1994; G. A. Kennett et al., Eur. J. Pharmacol., 164, 445-454,1989). This conviction is strongly reinforced by the clinical resultsobtained with mCPP, which behaves as a 5-HT_(2C) agonist and a 5-HT_(2A)antagonist (G. A. Kennett and G. Curzon, Br. J. Pharmacol., 94, 137-147,1988; I. Lucki et al., J. Pharmacol. Exp. Ther., 249, 155-164, 1989; P.J. Conn and E. Sanders-Bush, J. Pharmacol. Exp. Ther., 242, 552-557,1987), which possesses pronounced, anxiogenic properties and whichexacerbates depressive, aggressive and psychotic states in patients (D.L. Murphy et al., Psychopharmacology, 98, 275-282, 1989; J. H. Krystalet al., Soc. Neurosci. Abst., 17, 354, 1991; J. P. Seibyl, Soc.Neurosci. Abst., 15, 1236, 1989).

The compounds described in the present invention bind selectively to the5-HT_(2C) receptors with respect to the 5-HT_(2A) receptors and areantagonists which may thus be used in the treatment of diseases such asanxiety, depression, impulse disorders (such as aggression, B. A.McMillen, Drug. Develop. Persp., 12, 53-62, 1988), schizophrenia,appetite disorders (such as anorexia), cardiovascular diseases, sexualdysfunction (H. H. G. Berendsen et al., Psychopharmacology, 101, 57-61,1990), cerebral ischemic attacks (F. Granier et al., Acta Psychiatr.Stand., 72, 67-74, 1985; W. D. Dietrich et al., J. Cereb. Blood FlowMetabol., 9, 812-820, 1989; J. A. Zivin, Neurology, 34, 469-474, 1984;J. A. Zivin, Neurology, 35, 584-587, 1985; K. M. Bode-Greuel et al.,Stroke, 21, 164-166, 1990), drug abuse (T. F. Meert and P. A. J.Janssen, Drug. Develop. Res., 25, 39-53, 1992; T. F. Meert and P. A. J.Janssen, Drug. Develop. Res., 25, 55-66, 1992; E. M. Sellers et al.,Trends Pharmacol. Sci., 13, 69-75, 1992), sleeping disorders (C. Dugovicet al., Psychopharmacology, 97, 436-442, 1989) and migraine (D. L.Murphy et al., Psychopharmacology, 98, 275-282, 1989).

DETAILED DESCRIPTION OF THE INVENTION

More specifically, the present invention relates to the compounds offormula (I): ##STR2## in which: n represents 1 or 2,

R₁ represents a hydrogen atom or a linear or branched (C₁ -C₆) alkylgroup, a benzyl, acetyl, benzoyl, allyl, pyridinecarbonyl orpyridinemethyl group, a pyridineaminocarbonyl group, a linear orbranched (C₁ -C₆) phthalimidoalkyl group, a linear or branched (C₁ -C₄)(thiochroman-8-yloxy)alkyl group, a linear or branched (C₁ -C₄)(benzodioxanyloxy)alkyl group or a linear or branched (C₁ -C₆)acylaminoalkyl group, (wherein acyl is a benzoyl group, anaphtylcarbonyl group, a thienylcarbonyl group, a linear or branched (C₁-C₆) alkylcarbonyl group, a furylcarbonyl group, a pyrrolylcarbonylgroup, a pyridinylcarbonyl group, or a (C₃ -C₇) cycloalkylcarbonylgroup, each of these groups being optionally substituted with one ormore halogen atoms, trihalomethyl group, alkoxy group or hydroxy group),

R₂, R₃ or R₄, which may be identical or different, represent a hydrogenor halogen atom or a linear or branched (C₁ -C₆) alkyl group, a linearor branched (C₁ -C₆) alkoxy group, a hydroxyl, acetyl, aminocarbonyl,aminomethyl, cyano, nitro or amino group, a phenyl group (which may ormay not be substituted with one or more halogen atoms or hydroxylgroups, linear or branched (C₁ -C₆) alkoxy groups, linear or branched(C₁ -C₆) alkyl groups or trihalomethyl groups), a furyl group, apyridinyl group, a thienyl group or a pyrrolyl group, or alternatively,when they are located on adjacent carbons, R₂ and R₃ form, with thecarbon atoms which bear them, a furan or phenyl ring,

the isomers thereof and the addition salts thereof with apharmaceutically acceptable acid.

Among the pharmaceutically acceptable acids which may be mentioned,without any limitation, are hydrochloric acid, hydrobromic acid,sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulfonic acid, camphoric acid, etc.

The invention also relates to the process for the preparation of thecompounds of formula (I). In this process, when the compounds of formula(I) which it is desired to obtain are such that n=1, a pyrrolidine offormula (II) is used as starting material, in the form of a pair ofenantiomers or a pure enantiomer: ##STR3## in which R₂, R₃ and R₄ are asdefined in formula (I), which compound of formula (II), when it is inthe form of a pair of enantiomers, is reacted with lithium aluminumhydride in an inert solvent to give the pyrrolidine of formula (III):##STR4## in which R₂, R₃ and R₄ have the same meaning as in formula (I),

the methoxy function of which is converted into a hydroxyl function byreaction in the presence of sodium thioethoxide or boron tribromide, andwhich is then reacted with gaseous hydrogen chloride in the presence ofthionyl chloride, in chloroform medium, to give the compound of formula(IV): ##STR5## in which R₂, R₃ and R₄ have the same meaning as informula (I),

which compound is then cyclized in basic medium,

to give the compound of formula (I/a), a particular case of thecompounds of formula (I): ##STR6## in which R₂, R₃ or R₄ have the samemeaning as in formula (I),

compound of formula (I/a), the amine function of which may bedeprotected, if so desired, by catalytic hydrogenation,

to give the compound of formula (I/b), a particular case of thecompounds of formula (I): ##STR7## in which R₂, R₃ and R₄ have the samemeaning as in formula (I), which compound of formula (I/b) may bereacted, if so desired, with a halo derivative:

    R'.sub.1 X

in which:

X represents a halogen atom and

R'₁ represents a linear or branched (C₁ -C₆) alkyl group, an acetyl,benzoyl, pyridinecarbonyl, pyridinemethyl or 3-pyridineaminocarbonylgroup or a linear or branched (C₁ -C₆) phthalimidoalkyl group,

to give

either the compound of formula (I/c), a particular case of the compoundsof formula (I): ##STR8## in which R₂, R₃ and R₄ have the same meaning asin formula (I) and R"₁ represents a linear or branched (C₁ -C₆) alkylgroup, an acetyl, benzoyl, pyridinecarbonyl, pyridinemethyl or3-pyridineaminocarbonyl group or a linear or branched (C₁ -C₆)phthalimidoalkyl group,

or the compound of formula (V): ##STR9## in which R₂, R₃ and R₄ have thesame meaning as in formula (I) and alkCN represents a linear or branched(C₁ -C₆) cyanoalkyl group, compound of formula (V), the cyano group ofwhich is reduced to an amino group and which is reacted with a benzoylhalide (optionally substituted with a halogen atom),

to give the compound of formula (I/d), a particular case of thecompounds of formula (I): ##STR10## in which R₂, R₃ and R₄ have the samemeaning as in formula (I) and R"'₁ represents a linear or branched (C₁-C₆) benzoylaminoalkyl group (optionally substituted on the phenyl ringwith a halogen atom),

which compound of formula (I/a), (I/b), (I/c) or (I/d):

is optionally purified according to a standard purification technique,

whose enantiomers are separated, if so desired, according to a standardseparation technique,

and which is converted, where appropriate, into the addition saltsthereof with a pharmaceutically acceptable acid,

it being understood that the substituents R₂, R₃ and R₄ may beintroduced or modified throughout the synthesis of the compounds offormula (I), according to standard techniques in organic chemistry.

The compounds of formula (II) used as starting materials are preparedaccording to the process described by K. Achiwa et al. (Chem. Pharm.Bull., 33(7), 2762-2766, 1985) by performing a cycloaddition of anethylene of formula (IIa): ##STR11## in which R₂, R₃ and R₄ have thesame meaning as in formula (I),

with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine in the presenceof a catalyst such as trifluoroacetic acid. Depending on theconfiguration of the ethylene of formula (IIa) used, this cycloadditiongives a pyrrolidine of formula (II) in which the hydrogen atoms locatedin positions 3 and 4 are cis or trans relative to each other.

The compounds of formula (IV) may also be obtained, when the pyrrolidinepossesses hydrogen atoms in a cis position relative to each other, byperforming a cycloaddition according to the process described by K.Achiwa et al. (cited above) of a coumarin of formula (VI): ##STR12## inwhich R₂, R₃ and R₄ have the same meaning as in formula (I),

with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine, usingtrifluoroacetic acid as catalyst,

to give the compound of formula (VII): ##STR13## in which R₂, R₃ and R₄have the same meaning as in formula (I), which compound then undergoes areduction in the presence of lithium aluminum hydride,

to give the compound of formula (VIII): ##STR14## which is reacted withgaseous hydrogen chloride in the presence of thionyl chloride,

to give the compound of formula (IV).

In the process for the preparation of the compounds of formula (I), forwhich n=2, the starting material used is the compound of formula (IX):##STR15## in which R₂, R₃ and R₄ are as defined in formula (I), whichcompound is reacted, according to the method described in Can. J. Chem.,52, 2316, 1974, with methylmagnesium bromide and then withp-toluenesulfonic acid,

to give the compound of formula (X): ##STR16## in which R₂, R₃ and R₄have the same meaning as in formula (I), which compound is reacted withbenzylamine in the presence of formaldehyde,

to give the compound of formula (XI): ##STR17## in which R₂, R₃ and R₄have the same meaning as in formula (I),

which compound then undergoes a catalytic hydrogenation to give thecompound of formula (I/e), a particular case of the compounds of formula(I): ##STR18## in which R₂, R₃ and R₄ have the same meaning as informula (I),

which compound of formula (I/e) may be reacted, if so desired, with ahalo derivative of formula (XII):

    R'.sub.1A --X                                              (XII)

in which:

X represents a halogen atom and

R'_(1A) represents a linear or branched (C₁ -C₆) alkyl group, an acetyl,benzoyl, benzyl, pyridinecarbonyl, pyridinemethyl or3-pyridineaminocarbonyl group or a linear or branched (C₁ -C₆)phthalimidoalkyl group,

to give

either the compound of formula (I/f), a particular case of the compoundsof formula (I): ##STR19## in which R₂, R₃ and R₄ have the same meaningas in formula (I) and R"_(1A) represents a linear or branched (C₁ -C₆)alkyl group, an acetyl, benzoyl, benzyl, pyridinecarbonyl,pyridinemethyl or 3-pyridineaminocarbonyl group or a linear or branched(C₁ -C₆) phthalimidoalkyl group,

or the compound of formula (XIII): ##STR20## in which R₂, R₃ and R₄ havethe same meaning as in formula (I) and alkCN represents a linear orbranched (C₁ -C₆) cyanoalkyl group

compound of formula (XIII), the cyano group of which is reduced to anamine group and which is reacted with a benzoyl halide (optionallysubstituted with a halogen atom),

to give the compound of formula (I/g), a particular case of thecompounds of formula (I): ##STR21## in which R₂, R₃ and R₄ have the samemeaning as in formula (I) and R"'₁ represents a linear or branched (C₁-C₆) benzoylaminoalkyl group (optionally substituted on the phenyl ringwith a halogen atom),

which compound of formula (I/e), (I/f) or (I/g):

is optionally purified according to a standard purification technique,

whose enantiomers are separated, if so desired, according to a standardseparation technique,

and which is converted, where appropriate, into the addition saltsthereof with a pharmaceutically acceptable acid,

it being understood that the substituents R₂, R₃ and R₄ may beintroduced or modified throughout the synthesis of the compounds offormula (I), according to standard techniques in organic chemistry.

Another subject of the present invention is the pharmaceuticalcompositions containing, as active principle, at least one compound offormula (I) alone or in combination with one or more inert, non-toxicexcipients or vehicles.

Among the pharmaceutical compositions according to the invention, theremay more particularly be mentioned those which are suitable for oral,parenteral and nasal administration, simple or coated tablets,sublingual tablets, gelatin capsules, lozenges, suppositories, creams,ointments, dermal gels, etc.

The appropriate dosage varies depending on the age and weight of thepatient, the nature and severity of the complaint and the route ofadministration. The latter may be an oral, nasal, rectal or parenteralroute. In general, the unit dosage ranges between 1 and 500 mg for atreatment of 1 to 3 doses taken per 24 hours.

The examples which follow illustrate the invention and do not limit itin any way.

The structures of the compounds described in the examples were confirmedby the usual spectroscopic techniques.

The position of the hydrogen atoms located between the two heterocyclesis indicated in the following way: ##STR22##

The preparations described below lead to starting materials used duringthe synthesis of the compounds of the invention.

Preparation A: Methyl[trans-1-benzyl-4-(2-methoxyphenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described byK. Achiwa et al. (Chem. Pharm. Bull., 33(7), 2762-2766, 1985). To asolution containing 120 mmol of methyl trans-(2-methoxy)cinnamate and0.1 ml of trifluoroacetic acid in 150 ml of ethyl acetate cooled to 5°C., are slowly added 100 mmol ofN-benzyl-N-(methoxymethyl)trimethylsilylmethylamine. The reaction mediumis brought from 30° C. to 55° C. over 75 minutes. 0.75 g of potassiumcarbonate is then added and the mixture is kept stirring for 15 minutes.After filtration and evaporation of the solvents, the residue is takenup in 100 ml of ethyl acetate and the solution is brought to 50)C. 110mmol of oxalic acid dissolved in 100 ml of acetone are then added withvigorous stirring. The stirring is continued for 15 hours. The expectedproduct in the form of the oxalate is then obtained after filtration,and is rinsed with ether. The base is obtained after treatment of theoxalate with two equivalents of 1N potassium hydroxide.

Infrared: ν_(CO) (nujol)=1736 cm⁻¹

Preparation B:Methyl[trans-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2,6-dimethoxy)cinnamate as startingmaterial.

Infrared: ν_(CO) (nujol)=1736 cm⁻¹

Preparation C:Methyl[trans-1-benzyl-4-(2,5-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2,5-dimethoxy)cinnamate as startingmaterial.

Infrared: ν_(CO) (nujol)=1736 cm⁻¹

Preparation D:cis-2-Benzyl-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one

The expected product is obtained according to the process described inPreparation A, using coumarin as starting material.

Melting point (oxalate): 170°-175° C.

Preparation E:Methyl[cis-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl cis-(2,6-dimethoxy)cinnamate as startingmaterial.

Infrared: ν_(CO) (nujol)=1757 cm⁻¹

Preparation F:Methyl[trans-1-benzyl-4-(2-methoxy-4-chlorophenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2-methoxy-4-chloro)cinnamate asstarting material.

Infrared: ν_(CO) (nujol)=1755 cm⁻¹

Preparation G: cis-2-Benzyl-7-methoxy-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one

The expected product is obtained according to the process described inPreparation A, using 7-methoxycoumarin as starting material.

Melting point (oxalate): 182°-186° C.

Preparation H:Methyl[trans-1-benzyl-4-(2,4-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2,4-dimethoxy)cinnamate as startingmaterial.

Preparation I:Methyl[trans-1-benzyl-4-(2,3-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2,3-dimethoxy)cinnamate as startingmaterial.

Preparation J:cis-2-Benzyl-8-chloro-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one

The expected product is obtained according to the process described inPreparation A, using 6-chlorocoumarin as starting material.

Melting point (oxalate): 197° C.

Preparation K:Methyl[trans-1-benzyl-4-(2-methoxy-5-chlorophenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2-methoxy-5-chloro)cinnamate asstarting material.

Melting point (oxalate): 144° C.

Preparation L:cis-2-Benzyl-6-chloro-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one

The expected product is obtained according to the process described inPreparation A, using 8-chlorocoumarin as starting material.

Preparation M:Methyl[trans-1-benzyl-4-(2-methoxy-3-chlorophenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2-methoxy-3-chloro)cinnamate asstarting material.

Preparation N:Methyl[trans-1-benzyl-4-(2-methoxy-5-bromophenyl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-(2-methoxy-5-bromo)cinnamate asstarting material.

Preparation O:Methyl[trans-1-benzyl-4-(2-methoxynaphth-1-yl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-3-(2-methoxynaphth-1-yl)acrylate asstarting material.

Preparation P:Methyl[trans-1-benzyl-4-(1-methoxynaphth-2-yl)pyrrolidin-3-yl]carboxylate

The expected product is obtained according to the process described inPreparation A, using methyl trans-3-(1-methoxynaphth-1-yl)acrylate asstarting material.

Preparation Q:cis-16-Benzyl-13,14,15,17-tetrahydro-11-oxa-12-one-16-azacyclopenta[a]phenanthrene

The expected product is obtained according to the process described inPreparation A, using benzo[h]chroman-2-one as starting material.

Preparation R:cis-2-Benzyl-1,3,3a,11c-pentahydro-4-one-5-oxa-2-azacyclopenta[c]phenanthrene

The expected product is obtained according to the process described inPreparation A, using benzo[f]chromen-3-one as starting material.

EXAMPLE 1trans-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A: trans-1-Benzyl-3-hydroxymethyl-4-(2-methoxyphenyl)pyrrolidine

To 560 mmol of lithium aluminum hydride in 800 ml of tetrahydrofuran(THF), under a nitrogen atmosphere and at 5° C., are added 225 mmol ofmethyl [trans-1-benzyl-4-(2-methoxyphenyl)pyrrolidin-3-yl]carboxylate(described in Preparation A) dissolved in 500 ml of THF. After stirringfor 1 hour at 5° C., 139 ml of isopropyl alcohol are added slowly to theabove mixture, followed by 85.2 ml of saturated sodium chloridesolution. The mixture is stirred slowly at room temperature. Afterfiltration and evaporation of the solvents, the expected product isobtained.

Stage B: trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxyphenyl)pyrrolidine

To a previously prepared solution containing 96 mmol of sodiumthioethoxide in 140 ml of dimethylformamide (DMF) are added slowly 24mmol of the compound obtained in the above stage dissolved in 120 ml ofDMF. The mixture is maintained at 120° C. for 4 hours. After cooling,dilution with water, extraction with ether, drying and evaporation, theexpected product is obtained.

Stage C: trans-1-Benzyl-3-chloromethyl-4-(2-hydroxyphenyl)pyrrolidinehydrochloride

4.6 mmol of the compound obtained in the above stage are dissolved in100 ml of chloroform. After sparging for 10 minutes with hydrogenchloride gas, the reaction medium is brought to reflux and 13.8 mmol ofthionyl chloride are then added. The reflux is maintained until gaseousevolution has ceased. After evaporation of the solvent, the residue istaken up in ethanol and then evaporated. The expected product thenprecipitates in ether.

Stage D:trans-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

2.95 mmol of the compound obtained in the above stage are dissolved in100 ml of THF and 10 ml of hexamethylphosphorotriamide (HMPT). 4 ml of a1.6M solution of butyllithium in hexane are then added to the abovemixture. The mixture is kept stirring for 15 hours. After hydrolysis andevaporation of the solvents, the residue is taken up in water andextracted with ether. After drying and evaporation of the organicphases, the expected product is obtained by purification of the residueby column chromatography on silica, using a dichloromethane/methanolmixture (97/3) as eluent. The base is salified in hydrochloric ethanol.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  71.63  6.68       4.64 11.75                                      found       71.31  6.61       4.70 12.04                                      ______________________________________                                    

EXAMPLE 2trans-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A:trans-1-Benzyl-3-hydroxymethyl-4-(2,6-dimethoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage A of Example 1, using methyl[trans-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate,described in Preparation B, as starting material.

Stage B:trans-1-Benzyl-3-chloromethyl-4-(2,6-dimethoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage C of Example 1.

Stage C:trans-1-Benzyl-3-chloromethyl-4-(2,6-dihydroxyphenyl)pyrrolidine

To 5.8 mmol of the compound obtained in the above stage, dissolved in100 ml of dichloromethane, are added 29 ml of a 1M solution of borontribromide in dichloromethane. The mixture is maintained at reflux for 5hours. After cooling, 77 ml of ethyl ether and then 200 ml of saturatedsodium hydrogen carbonate solution are added. After extraction withether, the organic phases are washed with saturated sodium hydrogencarbonate solution, dried and evaporated. The expected product isobtained after purification of the residue by column chromatography onsilica, using a cyclohexane/ethyl acetate mixture (80/20) as eluent.

Stage D:trans-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage D of Example 1.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.09  6.03       4.41 11.17                                      found       67.73  6.35       4.41  4.27                                      ______________________________________                                    

EXAMPLE 3trans-2-Benzyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stages A and B:

These stages are identical to Stages A and B of Example 2.

Stage C:trans-1-Benzyl-3-chloromethyl-4-(2-hydroxy-6-methoxyphenyl)pyrrolidine

To 28.9 mmol of the compound obtained in the above stage, dissolved in200 ml of dichloromethane, are added 57.8 ml of a 1M solution of borontribromide in dichloromethane. The reaction medium is maintained atreflux for 45 minutes. After cooling and addition of 800 ml of water,the pH is brought to 10. After extraction with dichloromethane, dryingand evaporation, the residue is purified by column chromatography onsilica, using dichloromethane as eluent. The expected product isobtained after releasing with methanol and then with 1N sodiumhydroxide.

Stage D:trans-2-Benzyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

To 9.3 mmol of sodium hydride in 20 ml of THF is added a solutioncontaining 7.8 mmol of the compound obtained in the above stage in 20 mlof THF. The reaction medium is maintained at reflux for 3 hours and thenhydrolyzed. After extraction with ether, drying and evaporation, theexpected product is obtained by purification of the residue by columnchromatography on silica, using a dichloromethane/methanol mixture(95/5) as eluent.

Elemental microanalysis

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.77  6.68       4.22 10.68                                      found       68.34  6.47       4.51 11.21                                      ______________________________________                                    

EXAMPLE 4trans-9-Methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

2.2 mmol of the compound obtained in Example 3 in 100 ml of ethanol and30 ml of water are hydrogenated for 1 hour at 45° C. in the presence of70 mg of palladium-on-charcoal as catalyst. The expected product isobtained after evaporation of the solvents.

Elemental microanalysis

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  59.63  6.63       5.79 14.67                                      found       58.93  6.09       5.85 15.14                                      ______________________________________                                    

EXAMPLE 5trans-2-Acetyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

To 0.8 mmol of the compound obtained in Example 4 in 30 ml of chloroformare successively added 1.66 mmol of triethylamine and then 0.8 mmol ofacetyl chloride. After stirring for one hour at room temperature, thereaction medium is hydrolyzed. After extraction with chloroform, dryingand evaporation, the expected product is obtained after crystallizationof the residue from ethyl ether.

Elemental microanalysis:

    ______________________________________                                                       C %  H %                                                       ______________________________________                                        calculated       68.00  6.93                                                  found            67.21  6.57                                                  ______________________________________                                    

EXAMPLE 6trans-2-Propyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

To 3.3 mmol of the compound obtained in Example 4, dissolved in 20 ml ofacetonitrile and 10 ml of acetone, are successively added 6.6 mmol ofpotassium carbonate and then 3.3 mmol of 1-bromopropane. The reactionmedium is maintained at reflux for 15 hours. After cooling, filtration,hydrolysis and extraction with dichloromethane, the organic phases aredried and then evaporated. The expected product is obtained afterpurification of the residue by column chromatography on silica, using adichloromethane/methanol/aqueous ammonia mixture (90/10/0.5) as eluent.The base thus obtained is salified in hydrochloric ethanol.

Melting point: 233° C.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  63.48  7.81       4.94 12.45                                      found       63.53  7.86       4.84 12.74                                      ______________________________________                                    

EXAMPLE 7trans-2-Allyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol

To 3.3 mmol of the compound obtained in Example 4, dissolved in 30 ml ofchloroform, are successively added 6.6 mmol of triethylamine and then3.3 mmol of allyl bromide. The reaction medium is maintained at refluxfor one hour and then hydrolyzed with 1N sodium hydroxide. Afterextraction with chloroform, the organic phases are combined, dried andevaporated. The expected product is obtained after purification of theresidue by column chromatography on silica, using adichloromethane/methanol/aqueous ammonia mixture (95/5/0.5) as eluent.

Elemental microanalysis:

    ______________________________________                                                 C %        H %    N %                                                ______________________________________                                        calculated 63.15        6.35   3.87                                           found      61.59        6.41   3.88                                           ______________________________________                                    

EXAMPLE 8trans-2-[3-(4-Fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

Stage A:trans-2-Cyanomethyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

To 4.14 mmol of the compound obtained in Example 4, dissolved in 20 mlof acetonitrile, are successively added 8.28 mmol of potassium carbonateand then a solution containing 4.14 mmol of bromoacetonitrile in 20 mlof acetonitrile. The reaction medium is maintained at reflux for 15hours. After cooling and filtration the filtrate is hydrolyzed andextracted with dichloromethane. The organic phases are dried andevaporated, and the expected product is obtained after purification ofthe residue by column chromatography on silica, using adichloromethane/methanol mixture (98/2) as eluent.

Stage B:trans-2-(2-Aminoethyl)-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

1.5 mmol of the compound obtained in the above stage are added to asolution containing 3 mmol of lithium aluminum hydride in 15 ml of THFat 5° C. The reaction medium is stirred for 90 minutes at thistemperature. After addition of 0.17 ml of water, 0.25 ml of 2N sodiumhydroxide and then 0.46 ml of water, the medium is again stirred for 3hours and then filtered. The solvents are evaporated off and theexpected product is obtained after purification of the residue by columnchromatography on silica, using a dichloromethane/methanol/aqueousammonia mixture (80/20/2) as eluent.

Stage C:trans-2-[3-(4-Fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

To 1 mmol of the compound obtained in the above stage, dissolved in 80ml of chloroform at 5° C., are added 1 mmol of triethylamine and then,after stirring for 15 minutes, 1 mmol of para-chlorobenzoyl chloride.The reaction medium is maintained at 5° C. for 90 minutes and thenhydrolyzed using 1N sodium hydroxide. After extraction withdichloromethane, the organic phases are dried and evaporated, and theexpected product is obtained after purification of the residue by columnchromatography on silica. The base is then salified in hydrochloricethanol and the hydrochloride crystallizes from pentane.

Melting point: 202° C.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  61.99  5.95       6.88 8.71                                       found       61.85  5.91       6.92 8.52                                       ______________________________________                                    

EXAMPLE 9trans-2-Benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A:trans-1-Benzyl-3-hydroxymethyl-4-(2,5-dimethoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage A of Example 1, starting with methyl[trans-1-benzyl-4-(2,5-dimethoxyphenyl)pyrrolidin-3-yl]carboxylatedescribed in Preparation C.

Stage B:trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-5-methoxyphenyl)pyrrolidine

97 mmol of ethanethiol are added to a solution containing 97 mmol ofsodium hydride in 150 ml of DMF at 10° C. After stirring for 15 minutesat this temperature, 24 mmol of the compound obtained in Stage A areadded and the reaction medium is maintained at 120° C. for 3 hours.After cooling, hydrolysis, extraction with ether and then withdichloromethane, the organic phases are combined, dried and evaporated.The expected product is obtained after purification by columnchromatography on silica, using a dichloromethane/methanol mixture(95/5) as eluent.

Stage C:trans-1-Benzyl-3-chloromethyl-4-(2-hydroxy-5-methoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage C of Example 1, starting with the compound obtained in the abovestage.

Stage D:trans-2-Benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage D of Example 1, starting with the compound obtained in the abovestage.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.77  6.68       4.22 10.68                                      found       68.34  6.67       4.22 10.56                                      ______________________________________                                    

EXAMPLE 10trans-8-Methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inExample 4, starting with the compound obtained in Example 9.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  59.63  6.67       5.79 14.62                                      found       59.58  6.60       5.77 14.30                                      ______________________________________                                    

EXAMPLE 11trans-2-Propyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inExample 6, starting with the compound described in Example 10.Chromatographic purification is performed using adichloromethane/methanol mixture (95/5) as eluent, and gives thehydrochloride.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  63.48  7.88       4.94 12.49                                      found       63.05  7.66       4.97 12.51                                      ______________________________________                                    

EXAMPLE 12cis-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A: cis-1-Benzyl-3-hydroxyphenyl-4-(2-hydroxyphenyl)pyrrolidine

125 mmol ofcis-2-benzyl-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one(described in Preparation D) are added to a heterogeneous solutioncontaining 310 mmol of lithium aluminum hydride in 800 ml of THF at 5°C. The reaction medium is kept stirring for 3 hours at room temperatureand is then cooled to +10° C. 120 ml of ethyl alcohol, 120 ml of waterand then 40 ml of aqueous 40% sodium hydroxide solution are successivelyadded. After filtration of the salts, the filtrate is washed withsaturated sodium bicarbonate solution. The organic phase is dried and,after evaporation, gives the expected product.

Stage B: cis-1-Benzyl-3-chloromethyl-4-(2-hydroxyphenyl)pyrrolidinehydrochloride

The expected product is obtained according to the process described inStage C of Example 1, starting with the compound described in the abovestage.

Stage C:cis-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage D of Example 1, starting with the compound obtained in the abovestage.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  71.63  6.68       4.64 11.75                                      found       71.46  6.29       4.98 11.62                                      ______________________________________                                    

EXAMPLE 13 cis-1,3,3a,4,9b-Pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inExample 4, starting with the compound obtained in Example 12.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  62.41  6.67       6.62 16.75                                      found       61.77  6.47       6.43 16.54                                      ______________________________________                                    

EXAMPLE 14cis-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A: cis-1-Benzyl-3-hydroxymethyl-4-(2,6-dimethoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage A of Example 12, starting with methyl[cis-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylatedescribed in Preparation E.

Stage B: cis-1-Benzyl-3-chloromethyl-4-(2,6-dimethoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage C of Example 1, starting with the compound described in the abovestage.

Stage C: cis-1-Benzyl-3-chloromethyl-4-(2,6-dihydrophenyl)pyrrolidinehydrochloride

To 8.9 mmol of the compound obtained in the above stage, in 170 ml ofdichloromethane, are added 44.5 ml of a 1M solution of boron tribromidein dichloromethane. The reaction medium is maintained at reflux for 8hours and then treated with concentrated sodium hydroxide for one hour.The medium is then neutralized using hydrochloric acid. After extractionwith dichloromethane, the expected product is obtained afterpurification of the residue-by column chromatography on silica, using adichloromethane/methanol mixture (95/5) as eluent.

Stage D:cis-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage D of Example 1.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.03  6.34       4.41  4.26                                      found       67.43  6.50       4.38 10.66                                      ______________________________________                                    

EXAMPLE 15cis-2-Benzyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

11.6 mmol of the compound obtained in Example 14, in 50 ml of DMF, areadded to a solution containing 14 mmol of sodium hydride in 50 ml ofDMF. After stirring for 30 minutes, 11.6 mmol of methyl iodide areadded. After 1 hour at room temperature, followed by hydrolysis, thesolvents are evaporated off. The residue is then taken up in water.After extraction with ether, drying and evaporation, the expectedproduct is obtained after purification of the residue by columnchromatography on silica, using a cyclohexane/ethyl acetate mixture(75/25) as eluent.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.77  6.68       4.22 10.68                                      found       68.66  4.48       4.45 10.97                                      ______________________________________                                    

EXAMPLE 16cis-9-Methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inExample 4, starting with the compound described in Example 15.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  59.63  6.67       5.79 14.67                                      found       59.97  6.69       5.93 13.87                                      ______________________________________                                    

EXAMPLE 17cis-2-Acetyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole

The expected product is obtained according to the process described inExample 5, starting with the compound described in Example 16.

Elemental microanalysis

    ______________________________________                                                 C %        H %    N %                                                ______________________________________                                        calculated 68.00        6.93   5.68                                           found      67.89        6.94   5.49                                           ______________________________________                                    

EXAMPLE 18trans-2-Benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A:trans-1-Benzyl-3-hydroxymethyl-4-(2-methoxy-4-chlorophenyl)pyrrolidine

The expected product is obtained according to the process described inStage A of Example 1, using methyl[trans-1-benzyl-4-(2-methoxy-4-chlorophenyl)pyrrolidin-3-yl]carboxylate,described in Preparation F, as starting material.

Stage B:trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-4-chlorophenyl)pyrrolidine

The expected product is obtained according to the process described inStage B of Example 9, starting with the compound obtained in the abovestage.

Stage C:trans-1-Benzyl-3-chloromethyl-4-(2-hydroxy-4-chlorophenyl)pyrrolidine

The expected product is obtained according to the process described inStage C of Example 1, starting with the compound obtained in the abovestage.

Stage D:trans-2-Benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage D of Example 3 (using two equivalents of sodium hydride), startingwith the compound obtained in the above stage.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  64.29  5.70       4.17 21.09                                      found       64.25  5.72       4.03 21.27                                      ______________________________________                                    

EXAMPLE 19cis-2-[2-(Thiochroman-8-yloxy)ethyl]-1,3,3a,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

To 4.7mmol of cis-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride, described in Example 13, in 50 ml of acetonitrile areadded 9.4 mmol of potassium carbonate. After stirring for 15 min, 0.5mmol of potassium iodide and then 4.7 mmol of1-chloro-2-(thiochroman-8-yloxy)ethane dissolved in 50 ml ofacetonitrile are successively added. The reaction medium is maintainedat reflux for 24 hours and then evaporated, taken up in water, extractedwith dichloromethane and dried over magnesium sulfate before beingfiltered. The solvents are evaporated off. The crude product is purifiedby column chromatography on silica (eluent: CH₂ Cl₂ /MeOH: 97/3). Theproduct is then salified by a solution of HCl in ethanol.

Elemental microanalysis:

    ______________________________________                                        C %          H %    N %        Cl % S %                                       ______________________________________                                        calculated                                                                           65.41     6.49   3.47     8.78 7.94                                    found  65.08     6.31   3.58     8.23 8.23                                    ______________________________________                                    

EXAMPLE 20cis-2-[(Pyrid-3-yl)aminocarbonyl]-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

To 30 mmol of the product obtained in Example 16 in 50 ml ofdichloromethane is added 0.15 mmol of 3-pyridyl isocyanate. Afterstirring for 48 hours, the product is filtered off and thenchromatographed on a column of silica (eluent: dichloromethane/methanol:95/5). The product obtained is salified using ethanolic hydrochloricacid solution.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  59.75  5.57       11.61                                                                              9.80                                       found       60.06  5.56       11.38                                                                              8.94                                       ______________________________________                                    

EXAMPLE 21cis-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A:cis-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-4-methoxyphenyl)pyrrolidine

To 230 mmol of lithium aluminum hydride in 800 ml of THF, under anitrogen atmosphere, are added 180 mmol ofcis-2-benzyl-7-methoxy-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one, described in Preparation G, at +5° C. The reactionmedium is maintained at +10° C. for one hour before being hydrolyzed,and is filtered on Celite. The organic phase is dried and, afterevaporation, gives the expected product.

Stage B:cis-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

To 93 mmol of the compound obtained in Stage A in 700 ml oftetrahydrofuran (THF) are successively added 93 mmol of diethylazodicarboxylate and 93 mmol of triphenylphosphine. The reaction mediumis stirred for 3 hours at room temperature and the solvents are thenevaporated off. The crude product is purified by column chromatographyon silica (eluent: cyclohexane/ethyl acetate: 70/30). The product issalified using a solution of hydrochloric acid in ethanol.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.77  6.68       4.22 10.68                                      found       69.01  6.74       4.16 10.70                                      ______________________________________                                    

EXAMPLE 22trans-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A:trans-1-Benzyl-3-hydroxymethyl-4-(2,4-dimethoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage A of the Example 1, using the compound described in Preparation H.

Stage B:trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-4-methoxyphenyl)pyrrolidine

The expected product is obtained according to the process described inStage B of Example 1, using the compound obtained in the above stage asstarting material.

Stage C:trans-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage B of Example 21, starting with the compound obtained in the abovestage.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.77  6.68       4.22 10.68                                      found       68.44  6.59       4.49 10.77                                      ______________________________________                                    

EXAMPLE 23trans-2-Benzyl-6-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to Stages A, B and C ofExample 23, starting with the compound obtained from Preparation I.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.77  6.68       4.22 10.68                                      found       67.93  6.66       4.10 10.55                                      ______________________________________                                    

EXAMPLE 24cis-2-Benzyl-8-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

Stage A:cis-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-5-chlorophenyl)pyrrolidine

The expected product is obtained according to the process described inStage A of Example 12, using the compound described in Preparation J asstarting material.

Stage B:cis-2-Benzyl-8-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to the process described inStage B of Example 21, starting with the compound obtained in the abovestage.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  64.29  5.70       4.17 21.09                                      found       64.82  5.82       4.19 20.81                                      ______________________________________                                    

EXAMPLE 25trans-2-Benzyl-8-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to Stages A, B and C ofExample 22, starting with the compound obtained from Preparation K.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  64.29  5.70       4.17 21.09                                      found       64.01  6.01       4.22 21.05                                      ______________________________________                                    

EXAMPLE 26cis-2-Benzyl-6-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is prepared according to Stage A of Example 12 andthen Stage B of Example 21, starting with the compound obtained inPreparation L.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  64.29  5.70       4.17 21.09                                      found       63.72  5.59       4.26 24.16                                      ______________________________________                                    

EXAMPLE 27trans-2-Benzyl-6-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to Stages A, B and C ofExample 1 and then according to Stage D of Example 3, starting with thecompound obtained in Preparation M.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  64.29  5.70       4.17 21.09                                      found       64.22  5.45       4.01 21.47                                      ______________________________________                                    

EXAMPLE 28trans-2-Benzyl-8-bromo-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The expected product is obtained according to Stages A, B and C ofExample 1 followed by Stage D of Example 3, starting with the compoundobtained in Preparation N.

Elemental microanalysis:

    ______________________________________                                        C %           H %    N %        Br % Cl %                                     ______________________________________                                        calculated                                                                           56.79      5.03   3.68     20.99                                                                              9.31                                   found  57.14      5.19   3.48     20.00                                                                              9.18                                   ______________________________________                                    

EXAMPLE 29trans-2-Benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

9 mmol of the compound of Example 18 are dissolved in 10.4 ml ofdimethylformamide. 5 mmol of zinc cyanide and 0.3 mmol oftetrakis(triphenylphosphine)palladium are then added. The reactionmedium is maintained at 80° C. for 6 hours. After cooling, 30 ml oftoluene are added and the mixture is washed with twice 20 ml of 2Maqueous ammonia solution and then using saturated sodium chloridesolution. After evaporation of the solvents, the crude product issalified using a solution of hydrochloric acid in ethanol.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  69.83  5.86       8.57 10.85                                      found       69.41  5.77       8.53 10.83                                      ______________________________________                                    

EXAMPLE 30trans-8-Cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

17.2 mmol of the compound obtained in Example 29 in 130 ml of ethanoland 40 ml of water are hydrogenated for 24 hours at 40° C. in thepresence of 500 mg of palladium-on-charcoal as catalyst. Afterevaporation of the solvents, the expected product is obtained.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  60.89  5.54       11.83                                                                              14.98                                      found       60.44  5.52       11.45                                                                              14.26                                      ______________________________________                                    

EXAMPLE 31trans-2-Propyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride

The compound obtained in Example 30 is treated according to theprocedure described for Example 6.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  64.63  6.87       10.05                                                                              12.72                                      found       63.93  6.78        9.53                                                                              12.21                                      ______________________________________                                    

EXAMPLE 32trans-2-Benzyl-1,2,3,3a,4,11c-hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrenehydrochloride

The expected product is obtained according to Stages A, B and C ofExample 1 followed by Stage D of Example 3, starting with the compoundobtained in Preparation O.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  75.10  6.30       3.98 10.08                                      found       74.51  6.25       4.16 10.02                                      ______________________________________                                    

EXAMPLE 33trans-1,2,3,3a,4,11c-Hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrenehydrochloride

The product obtained in Example 32 is treated according to the procedureof Example 30.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.83  6.16       5.35 13.54                                      found       68.49  6.25       4.99 13.47                                      ______________________________________                                    

EXAMPLE 34trans-16-Benzyl-12,13,14,15,16,17-hexahydro-11-oxa-16-aza-cyclopenta[a]phenanthrenehydrochloride

The expected product is obtained according to Stage A of Example 1 andthen treated according to the procedures described in Stage C of Example2 and Stage B of Example 21, starting with the compound of PreparationP.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  75.10  6.30       3.98 10.08                                      found       74.89  6.30       3.93 10.19                                      ______________________________________                                    

EXAMPLE 35cis-16-Benzyl-12,13,14,15,16,17-hexahydro-11-oxa-16-aza-cyclopenta[a]phenanthrenehydrochloride

The expected product is obtained according to Stages A and B of Example21, starting with the compound obtained in Preparation Q.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  75.10  6.30       3.98 10.08                                      found       74.53  6.38       3.85 10.02                                      ______________________________________                                    

EXAMPLE 36cis-12,13,14,15,16,17-Hexahydro-11-oxa-16-aza-cyclopenta[a]phenanthrenehydrochloride

The expected product is obtained according to the process described forExample 30, starting with the compound of Example 35.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.83  6.16       5.35 13.54                                      found       68.41  6.22       5.56 13.46                                      ______________________________________                                    

EXAMPLE 37cis-2-Benzyl-1,2,3,3a,4,11c-hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrenehydrochloride

The expected product is obtained according to Stages A and B of Example21, starting with the compound obtained in Preparation R.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  75.10  6.30       3.98 10.08                                      found       75.13  6.30       4.01  9.88                                      ______________________________________                                    

EXAMPLE 38cis-1,2,3,3a,4,11c-Hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrenehydrochloride

The expected product is obtained according to the process described forExample 30, starting with the compound of Example 37.

Elemental microanalysis:

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        calculated  68.83  6.16       5.35 13.54                                      found       68.25  6.11       5.43 13.19                                      ______________________________________                                    

Pharmacological Study of the Compounds of the Invention EXAMPLE 39Measurement of the in vitro affinity for the 5-HT_(2C) and 5-HT_(2A)receptors

Methods

The procedures described for the studies of the binding to the 5-HT_(2A)and 5-HT_(2C) receptors are exactly those described by H. Canton et al.(Eur. J. Pharmacol., 191, 93, 1990) and M. J. Millan et al. (J.Pharmacol. Exp. Ther., 262, 451-463, 1992). For 5-HT_(2A) : rat frontalcortex/[³ H]-ketanserin (1.0 nM). For 5-HT_(2C) : pig cerebral plexus/[³H]-mesulergine (1.0 nM). The 50% inhibitory doses (ID₅₀) are determinedby regression analysis and the pKi values are calculated as follows:##EQU1## [L]=concentration of the Kd-Kd=dissociation constant Results

The results obtained with the reference compounds and the compounds ofthe invention are combined in the table below.

SB 200,646 showed a modest affinity for the 5-HT_(2C) receptors of theorder of 200 nM and had only a weak affinity for the 5-HT_(2A) sites.Its selectivity is thus 6 for the 5-HT_(2C) sites. On the other hand,MDL 100,907 showed a very considerable selectivity of the order of 200for the 5-HT_(2A) receptors, for which it has a very strong affinity.

The compounds of the invention have a greater affinity for the 5-HT_(2C)receptors than the reference compound SB 200,646. Furthermore, they havea better selectivity for the 5-HT_(2C) receptors with respect to the5-HT_(2A) receptors.

There may more particularly be mentioned the compounds of Examples 19and 20, which are 9 and 14 times more powerful antagonists respectivelythan the reference compound SB 200,646, and the compounds of Examples 6and 7, which have a selectivity which is twice that of the referencecompound SB 200,646.

    ______________________________________                                                   5-HT.sub.2C                                                                              5-HT.sub.2A                                                                            5-HT.sub.2A /5-HT.sub.2C                       Compound   Ki (nM)    Ki (nM)  affinity ratio                                 ______________________________________                                        Example 2  195        490      2.5                                            Example 3  48         269      5.6                                            Example 4  431        3468     8.0                                            Example 6  104        1738     16.7                                           Example 7  120        1820     15.2                                           Example 8  107        95       0.9                                            Example 9  468        1097     2.3                                            Example 10 2188       >10000   >4.8                                           Example 11 4074       >10000   >2.3                                           Example 12 832        3549     4.3                                            Example 13 3090       >10000   >3.33                                          Example 14 218.8      1096     5.00                                           Example 15 36.3       389.0    10.7                                           Example 16 263        3311     12.6                                           Example 18 871        1867     2.1                                            Example 19 22         155      7.0                                            Example 20 14.4       102      7.1                                            Example 21 871        617      0.7                                            Example 22 478        170      3.6                                            Example 24 38         107      2.8                                            Example 33 51         107      2.1                                            Example 34 776        1479     1.9                                            Example 35 331        955      2.9                                            Example 36 25.7       257      10                                             Example 37 155        1349     8.7                                            Example 38 22.9       97.7     4.3                                            SB 200,646 204.0      1318     6.5                                            MDL 100,907                                                                              107.2      0.59     0.006                                          ______________________________________                                    

Each value represents the average of two to four determinations.

EXAMPLE 40 Pharmaceutical composition

    ______________________________________                                        Formula for the preparation of 1000 tablets                                   containing a 10 mg dose:                                                      ______________________________________                                        Compound of Example 16                                                                           10 g                                                       Hydroxypropylcellulose                                                                           2 g                                                        Wheat starch       10 g                                                       Lactose            100 g                                                      Magnesium stearate 3 g                                                        Talc               3 g                                                        ______________________________________                                    

We claim:
 1. A compound selected from those of formula (I): ##STR23## inwhich: n represents 1,R₁ represents hydrogen, linear or branched (C₁-C₆) alkyl, benzyl, acetyl, benzoyl, allyl, pyridinecarbonyl,pyridinemethyl, pyridineaminocarbonyl, linear or branched (C₁ -C₆)phthalimidoalkyl, linear or branched (C₁ -C₄)(thiochroman-8-yloxy)alkyl, linear or branched (C₁ -C₄)(benzodioxanyloxy)alkyl, or linear or branched (C₁ -C₆) acylaminoalkylwherein acyl is benzoyl, naphthylcarbonyl, thienylcarbonyl, linear orbranched (C₁ -C₆) alkylcarbonyl, furylcarbonyl, pyrrolylcarbonyl,pyridinylcarbonyl, or (C₃ -C₇) cycloalkylcarbonyl, each of these acylgroups being optionally substituted with one or more halogen,trihalomethyl, alkoxy or hydroxyl, R₂, R₃ or R₄, which may be identicaland different, represent hydrogen, halogen, linear or branched (C₁ -C₆)alkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl, acetyl,aminocarbonyl, aminomethyl, cyano, nitro, amino, phenyl which may or maynot be substituted with one or more halogen, hydroxyl, linear orbranched (C₁ -C₆) alkoxy, linear or branched (C₁ -C₆) alkyl, ortrihalomethyl, or R₂, R₃, and R₄ represent furyl, pyridinyl, thienyl orpyrrolyl,the optical isomers thereof and the addition salts thereof witha pharmaceutically-acceptable acid.
 2. A compound of claim 1, in whichR₁ represents a benzyl group, the optical isomers thereof and theaddition salts thereof with a pharmaceutically-acceptable acid.
 3. Acompound of claim 1, in which at least one of the groups R₂, R₃ and R₄represents a linear or branched (C₁ -C₆) alkoxy group or a hydroxylgroup, the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable acid.
 4. A method for treating a livinganimal body afflicted with a condition requiring an antagonist of the5-HT_(2C) receptors comprising the step of administering to the livingbody an amount of a compound of claim 1 which is effective foralleviation of said condition.
 5. A pharmaceutical compositioncomprising as active principle an effective 5-HT_(2C) receptorantagonistic amount of a compound as claimed in claim 1, together withone or more pharmaceutically-acceptable excipients or vehicles.
 6. Acompound of claim 1 selected from the group consistingoftrans-2-[3-(4-fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole;trans-2-benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride;trans-2-benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride; andtrans-2-benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride.
 7. A method of claim 4 wherein the compound is selectedfrom the group consistingof:trans-2-[3-(4-fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole;trans-2-benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride;trans-2-benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride; andtrans-2-benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride.
 8. A composition of claim 5 wherein the compound isselected from the group consistingof:trans-2-[3-(4-fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole;trans-2-benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride;trans-2-benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride; andtrans-2-benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrolehydrochloride.